SUMMARY: Naive T cells have the potential to differentiate into effector cells with a range of functions that aid in clearing pathogens as well as long-lived memory cells that provide protection from reinfection. CD4+ effector or T helper cells are defined by the cytokines they produce, which mediate the activity of innate, B cell, and CD8+ T cell immunity. The presence of numerous CD4+ T helper subsets has complicated the ability to define the relationship between effector and memory-precursor populations and identify the molecular mediators required to support the formation of CD4+ protective immunity. As CD4+ T cell help is required to sustain CD8+ T cell memory in many contexts, to support high-affinity memory B cell responses, and to direct activity of innate cells, we will seek to define the CD4+ memory T cell population(s) and their precursor(s) as well as the transcriptional networks driving differentiation and homeostasis of this vital component of immune memory. Further, our studies will explore the distinct differentiation requirements for CD4+ memory T cell populations that reside in non-lymphoid tissues and circulating memory populations. Tissue-resident memory cells are of particular interest in the context of vaccination as they provide essential sentinel protection at barrier surfaces, and, are now clearly understood to be among the `first responders' in many infection settings. Using single-cell analyses of protein and gene expression, genomic and computational approaches, and in vivo functional screens as well as traditional adoptive transfers of cells that can report expression of or are mutant for candidate regulators, we will comprehensively study CD4+ memory T cell formation in response to viral infection. These studies will provide the basis to exploit the protective capacity of this vital memory T cell population and modulate activity in the context of immunopathology. Direct targeting of specific transcriptional regulators during vaccination holds promise as a novel strategy in the control of induced immunity. !